Archambeault Denise R, Yao Humphrey Hung-Chang
Department of Comparative Biosciences, University of Illinois, Urbana, Illinois.
Biol Reprod. 2014 Mar 20;90(3):62. doi: 10.1095/biolreprod.113.111393. Print 2014 Mar.
As the central component of canonical TGFbeta superfamily signaling, SMAD4 is a critical regulator of organ development, patterning, tumorigenesis, and many other biological processes. Because numerous TGFbeta superfamily ligands are expressed in developing testes, there may exist specific requirements for SMAD4 in individual testicular cell types. Previously, we reported that expansion of the fetal testis cords requires expression of SMAD4 by the Sertoli cell lineage. To further uncover the role of Smad4 in murine testes, we produced conditional knockout mice lacking Smad4 in either Leydig cells or in both Sertoli and Leydig cells simultaneously. Loss of Smad4 concomitantly in Sertoli and Leydig cells led to underdevelopment of the testis cords during fetal life and mild testicular dysgenesis in young adulthood (decreased testis size, partially dysgenic seminiferous tubules, and low sperm production). When the Sertoli/Leydig cell Smad4 conditional knockout mice aged (56- to 62-wk old), the testis phenotypes became exacerbated with the appearance of hemorrhagic tumors, Leydig cell adenomas, and a complete loss of spermatogenesis. In contrast, loss of Smad4 in Leydig cells alone did not appreciably alter fetal and adult testis development. Our findings support a cell type-specific requirement of Smad4 in testis development and suppression of testicular tumors.
作为经典TGFβ超家族信号传导的核心组成部分，SMAD4是器官发育、模式形成、肿瘤发生及许多其他生物学过程的关键调节因子。由于众多TGFβ超家族配体在发育中的睾丸中表达，因此在单个睾丸细胞类型中可能对SMAD4有特定需求。此前，我们报道胎儿睾丸索的扩展需要支持细胞谱系表达SMAD4。为了进一步揭示Smad4在小鼠睾丸中的作用，我们制备了在睾丸间质细胞中或在支持细胞和睾丸间质细胞中同时缺乏Smad4的条件性敲除小鼠。支持细胞和睾丸间质细胞中同时缺失Smad4会导致胎儿期睾丸索发育不全以及成年早期轻度睾丸发育异常（睾丸尺寸减小、生精小管部分发育异常、精子产量低）。当支持细胞/睾丸间质细胞Smad4条件性敲除小鼠变老（56至62周龄）时，睾丸表型会加剧，出现出血性肿瘤、睾丸间质细胞瘤以及完全丧失精子发生。相比之下，仅睾丸间质细胞中缺失Smad4并不会明显改变胎儿和成年睾丸的发育。我们的研究结果支持了Smad4在睾丸发育和抑制睾丸肿瘤中存在细胞类型特异性需求。
